In certain embodiments, this invention sets forth compositions, methods, and uses regarding a nanoemulsion composition that comprise or consist essentially of a fat-soluble vitamin K and can therapeutically replace Phytonadione Injectable Emulsion, USP.
Vitamin K includes a group of lipophilic, hydrophobic vitamins that are required for blood coagulation. Chemically, they are 2-methyl-1,4-naphthoquinone derivatives. Vitamin K1 is also known as phytonadione (also called phylloquinone or phytomenadione). Vitamin K1 is found chiefly in leafy green vegetables and vitamin K2 is found in meat, eggs, dairy, and natto, the Japanese fermented bean preparation. In adults, gut bacteria normally produce significant amounts of usable vitamin K. In newborns, the gut has not yet been colonized with bacteria. Therefore, standard medical practice in the US is to administer vitamin K injections prophylactically to prevent haemorrhagic disease of the newborn. Similarly, patients undergoing treatment with large doses of antibiotics may develop vitamin K deficiency due to a reduced intestinal flora. An injectable vitamin K preparation can be also used to prevent or treat this type of vitamin K defficiency.
The current vitamin K preparation for injection available in the U.S. is listed in the US Pharmacopeia as Phytonadione Injectable Emulsion, USP (“PIE-USP”). It is approved by the FDA for treating blood coagulation disorders including (1) prophylaxis and therapy of hemorrhagic disease of the newborn; (2) anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives; (3) hypoprothrombinemia due to antibacterial therapy; (4) hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K; and (5) other drug-induced hypoprothrombinemia. An estimated 8 million doses of PIE-USP are administered in the US every year with about 50-60% of the doses used in newborns. The American Academy of Pediatrics Committee on Nutrition recommends that 0.5 to 1.0 mg Vitamin K1 be administered to all newborns shortly after birth.
Since vitamin K is insoluble in water, a number of solubilization methods have been tried to dissolve it for injection. PIE-USP is an aqueous solution that contains polyoxyethylated fatty acid, which is a strong detergent (also known as Cremophor), to solubilize vitamin K. Originally developed by Merck & Co under the brand name of “AquaMEPHYTON®”, Phytonadione Injectable Emulsion, USP actually does not contain any oil and is therefore not a true emulsion, despite what its name suggests. Other surfactants have also been used to solubilize vitamin K, including, for example, HCO-60 (Nikko Chemical Co., Ltd., Japan), which is also a high HLB (i.e., with a Hydrophobic-Lipophilic Balance value >7) surfactant or detergent that is similar to Cremophor.
The injection of a high HLB surfactant or detergent such as Cremophor, polysorbate 80 or HCO-60 can cause hypersensitivity reactions or, more severely, anaphylaxis. The potential for such sometimes fatal reactions is well documented for all Cremophor-containing drugs, such as TAXOL® and cyclosporine A. For this reason, the package insert for PIE-USP bears an FDA black box warning noting that the drug may be very unsafe or even fatal if injected intravenously or intramuscularly (AquaMEPHYTON® package insert. Merck & Co., February 2002). Moreover, Cremophor has been linked to childhood cancer (Golding, J. 1992. BMJ 305: 341) and acute lymphoblastic leukemia (von Kries, R. 1998. BMJ 316: 161; Wariyar, U. et al. 2000. Arch Dis Child Fetal Neonatal Ed 82: F64). Needless to say, such associations would be terrifying to both parents and physicians. Furthermore, Cremophor-containing PIE-USP has potential to cause pain and irritation at the injection site when injected subcutaneously or intramuscularly and may cause gastrointestinal disturbance if taken orally. Such irritation is believed related to the hemolytic nature of Cremophor.
A safer replacement for PIE-USP is needed. Nevertheless, even after many years of PIE-USP usage, a new and safer composition has still not been developed in the US. The investment and return economics related to the small market size and high cost of obtaining marketing approval for such a new composition are key reasons why a new and safer composition has not yet been developed for the US market. The current market size for PIE-USP is about $25 million per year, which is too small for most drug developers to justify the cost of obtaining a new drug approval in the US (estimated to be several hundred million dollars). This unfavorable return on investment ratio discourages drug developers from bringing a safer vitamin K injectable product to the market while patients, including nearly every newborn in the US, continue to be exposed to potentially severe adverse effects of Cremophor.
This application discloses embodiments of a new nanoemulsion composition that could make a safer replacement for PIE-USP commercially feasible by significantly reducing its development cost. By having bioequivalent properties, the new composition may be approved by the FDA on the basis of a single human pharmacokinetic study demonstrating their bioequivalence. Such abbreviated approval requirements based on pharmacokinetic and bioequivalent properties is codified in US Federal Law as a 505(b)(2) New Drug Application (NDA). An abbreviated and accelerated market approval may require only about 30 patients, which translates into a significant reduction in development cost making the development of a safer replacement for PIE-USP a commercially viable possibility.
Preferably, the nanoemulsion composition disclosed herein has a surprising pharmacokinetic profile that is nearly identical to the PIE-USP (i.e., “bioequivalent”). This new composition achieves this property without the use of Cremophor or any other high HLB surfactant for solubilizing vitamin K.
More preferably, the nanoemulsion composition disclosed herein does not cause hypersensitivity or anaphylactic reactions, is not hemolytic (and therefore has a low potential for causing pain and irritation at the injection site), and has stability comparable to PIE-USP (Example 12). These safety and stability features, when combined with their bioequivalent properties, form the basis for a commercially feasible safe replacement for PIE-USP and sets these nanoemulsion embodiments apart from any other compositions in the prior art.
Ohasi, et al. (U.S. Pat. No. 4,840,970) discloses an aqueous solution composition for vitamins A, E and K comprising hydrogenated lecithin in the amount of 0.1 to 12 parts by weight of the vitamin. The composition disclosed by Ohasi is an “aqueous solution” that contains no oil and is therefore not an oil-in-water emulsion or nanoemulsion by strict definition. The disclosed hydrogenated lecithin-to-vitamin K weight ratio of 0.1:1 to 12:1 is considerably lower than the 13:1 to 25:1 of phospholipid-to-vitamin K weight ratio used for the nanoemulsion embodiment. Moreover, Ohasi did not teach any method or composition for achieving bioequivalence to PIE-USP.
Ida et al. (U.S. Pat. No. 5,021,570) disclosed another aqueous solution comprising hydrogenated lecithin, a triester of glycerol with fatty acids having 8 to 12 carbons, the monoester of the same, a triester of glycerol with oleic acid, stearic acid or palmitic acid, and water. The composition so disclosed was an “aqueous solution” and was not an emulsion or nanoemulsion. The disclosed concentration for hydrogenated lecithin was about 0.05 to 3%, which is considerably lower than the 4-20% concentration of phospholipid used for the nanoemulsion embodiments of the present invention. Furthermore, the exemplary nanoemulsion embodiments do not contain any monoester of glycerol. Moreover, Ida did not teach any method or composition for achieving bioequivalence to PIE-USP.
Vitamin K is photosensitive and can decompose in the presence of light. Matsuda, et al. (U.S. Pat. No. 5,180,747) teaches a method of protecting vitamin K in the presence of light and preventing the reduction in activity of a fat-soluble vitamin K composition that comprises α-carotene, γ-carotene, lycopene, and canthaxanthin. However, the exemplary nanoemulsion embodiments do not contain any of these ingredients.
Kaneshiro (JP 11438300) discloses oil-in-water emulsion compositions for vitamin K1 and K2 comprising egg lecithin and oil, wherein a weight ratio of the phospholipid to vitamin K is about 0.5:1 to 10:1 and preferably 1:1 to 5:1. Preferred embodiments of the present invention's nanoemulsion composition comprise vitamin K, a phospholipid component and an oil component, but with a weight ratio of phospholipid to vitamin K of about 13:1 to 25:1.